Hypertension is present in up to 80% of patients with end stage renal disease (ESRD) and is a major risk factor for the excessive cardiovascular morbidity and mortality among these patients. An additional risk factor present in ESRD is overactivity of the sympathetic nervous system, which may not only contribute to the hypertension but could also accelerate the progression of heart disease independent of the rise in blood pressure (BP). Thus, the sympathetic nervous system constitutes a putative new drug target for arresting the progression,,of hypertensive heart disease in ESRD. To develop effective countermeasures, it is important to identify the signal driving the sympathetic overactivity. One potential signal involves the accumulation of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Increasing functional evidence indicates that nitric oxide (NO) is not only an endothelium-dependent vasodilator but also a key signaling molecule involved in the tonic restraint of central sympathetic outflow. Since ADMA is in part cleared by the kidney, abnormally high levels accumulate in patients with ESRD. Thus, our central hypothesis is that accumulation of ADMA constitutes a major mechanism for the sympathetic overactivity and hypertension in patients with ESRD. To test this hypothesis, we will first directly measure muscle and skin sympathetic nerve activity (SNA) in healthy subjects with normal renal function to determine if experimental NOS inhibition increases SNA. Second, we will measure muscle and skin SNA in ESRD patients to determine if NO deficiency produced by increases in the endogenous NOS inhibitor ADMA is a major mechanism mediating the sympathetic overactivity and hypertension in ESRD. Specifically, we will determine if restoration of NO production with the infusion of L-arginine reduces SNA and BP. These studies will provide novel information about the sympathoinhibitory role of centrally produced NO in humans and provide a conceptual framework for clinical research to determine if the NO pathway constitutes an effective therapeutic target for the sympathetic overactivity and hypertension in patients with ESRD as well as other forms of disease with elevated plasma ADMA concentrations. Although elevated plasma ADMA has been shown to be a strong and independent predictor of overall mortality and cardiovascular outcome in ESRD patients, the cardiovascular effects of this systemic increase in ADMA remain unclear. Identifying a role for ADMA-induced NOS inhibition in increasing sympathetic outflow has major therapeutic implications to help reduce the extremely high prevalence of hypertension and cardiovascular morbidity in patients with ESRD. [unreadable] [unreadable] [unreadable]